ABSTRACT ? METHODOLOGY CORE Rheumatic and musculoskeletal diseases (RMDs), including osteoarthritis (OA), are major sources of pain and disability worldwide, yet significant gaps persist in our understanding of disease mechanisms and optimal treatment strategies for many RMDs. There is a critical need for high quality, advanced studies that will meaningfully improve our understanding of RMDs, particularly phenotypes that predict disease progression and treatment response. The Methodology Core of our University of North Carolina (UNC) Core Center for Clinical Research (CCCR) is uniquely equipped to provide a comprehensive suite of resources that will optimize clinical RMD studies locally, nationally and internationally. Our Methodology Core includes researchers with expertise in biostatistics and bioinformatics, epidemiological studies, clinical trials, training and mentoring, health disparities, intervention development, dissemination and implementation, along with RMD-specific expertise in areas including imaging, biomarkers, and treatment guidelines. We have a long, successful track record of designing and conducting seminal clinical RMD studies (particularly in OA), developing junior investigators into independent researchers, fostering national/international collaborations, delivering methodological training to the RMD research community, leading national and international RMD- focused work groups and communicating, advocating, and influencing public policy. Building and expanding on our proven processes and established infrastructure, the Methodology Core will continue to serve the RMD research community by achieving three specific aims. First, we will support the development and application of advanced and innovative statistical methodologies (e.g., supervised and unsupervised machine learning, outcome-weighted learning, Markov state modeling, high dimensional low sample size methods, heterogeneity of treatment effects) to clinical RMD studies; this will include support for our Phenotyping and Precision Medicine Core. Second, we will provide comprehensive, rigorous multidisciplinary methodological resources that support and advance clinical RMD research within the CCCR base, as well as through collaborative efforts locally, nationally and internationally. Third, we will deliver state-of-the-art educational materials and training that prepare researchers, both locally and nationally/internationally, to conduct high quality, innovative clinical studies on RMDs. Collectively, these aims will provide services to a large, international clinical RMD research community, resulting in studies that lead to significant improvements in care and outcomes for the many patients living with RMDs.